The goal of the Transdisciplinary Theoretical Synthesis and Development Core (Theory Core, for short) is to strengthen the theoretical bases of CDUHR Investigators' research and, more generally, of global research in HIV epidemiology, prevention, and care for substance users (SUs) and those in their communities. In CDUHR-III, the Theory Core focused heavily on training and consultation about the relative merits of appropriate individual/ psychological and social theories for studying individual- and social-level influences and correlates of HIV risk, prevention, adherence, and retention for SUs. However, HIV research and interventions now face serious problems that require a shift beyond reliance on the psychosocial theoretical approaches that have dominated HIV prevention and care for the last three decades. Despite many new promising behavioral and biomedical prevention and treatment interventions, the HIV and substance use epidemic continues to spread at unacceptable rates in the U.S. and internationally. Further, widespread ongoing tumultuous economic, social and political environments may lead to large increases in high-risk substance use, high-risk networks or contexts, and high-risk sex, and to renewed HIV outbreaks based on these changes or on other structural barriers to maintaining adequate antiretroviral therapy. The complexity of these processes is increased by the rapidity of scientific discovery (including social/behavioral and biomedical prevention and treatment strategies) and the resulting changes in the organization and staffing of HIV prevention and care programs. Yet new clinical and prevention approaches are, of necessity, embedded not only in behavioral complexities but in social, economic and cultural complexities and we need to understand the mechanisms through which socioeconomic contexts affect both clinical/biomedical and behavioral interventions. Training and consultation must incorporate theoretical frameworks that can address emerging problems and perspectives such as these. Prospects for vaccines, biomedical prevention, and possibly microbicides look promising, and clinical science has found therapeutic regimens for HIV and related diseases that have prolonged and transformed infected peoples' lives. Yet there are gaps between intrinsic efficacy and effectiveness when translated into practice. The Seek, Test, Treat and Retain (STTR) strategy seeks to extend these clinical benefits to larger numbers of people, and recent research suggests that STTR may reduce community viral load enough to decrease HIV transmission and, in time, end the epidemic.[1,2] Existing research, however, falls short of convincingly ascertaining the size and variation in the effectiveness of STTR strategies for preventing HIV transmission in substance-using populations and their communities, in part because it has used theoretical models that assume random mixing while ignoring network effects (like the firewall restriction on acute HIV transmission epidemics[3]). New network modeling techniques like Exponential Random Graph Modeling (ERGM) offer methods to incorporate network structural features into current analyses,[4-6] but have yet to be applied to existing data sets that include SUs. The Theory Core seeks to bring graph modeling and dynamic simulation capabilities to CDUHR investigators. The increasing need for transdisciplinary research, which can encompass multiple levels of influence on the HIV-substance use epidemic, poses many challenges for CDUHR and other researchers nationally and internationally. Theoretical training, innovation, and guidance can make such research more successful. Further, theoretical development is needed to incorporate a focus in research on both socioeconomic change' and the organizational complexities created by rapid scientific advance. Moreover, we need theoretical development in support of a systemic theory of research translation in a time of rapid social, political, economic and scientific change.